Relatively few disease states can be satisfactorily managed by treatment with a single agent. Thus multiple drug therapy is prevalent and drug interactions are a clinical reality that cannot be ignored. A program is proposed to probe the fundamental mechanisms of five representative catetories of drug interactions. Stereoselective interactions with racemic drugs, will be examined in projects I and II. Project I will study stereoselective alterations in the metabolic profiles of the oral anticoagulants warfarin and phenprocoumon induced by sulfinpyrazones, pehnylbutazone, cimetidine and rifampin. Project II examines the effects of specific inhibitors (cimetidine, chlorpromazine, valproic acid and hydralazine) on the erantiomeric profiles of propranolol and metoprolol and some of their metabolites. The role of the metabolites of a primary drug affecting the disposition of a secondary drug will be studied in project III. To this end, the effects of valproic acid and its metabolites on the disposition of phenobarbital and carbamazepine will be examined. Project IV will examine drug interactions which occur when one drug modulates the cytotoxicity of a second drug by alterating concentrations of reactive metabolites of the second drug in a target tissue. Proposed studies will examine the mechanisms of the known interactions between acetaminophen and ascorbic acid, ethanol, adriamycin, p ropoxyphene, cimetidine and valproic acid. Another category of interactions involves the competition for an endogenous cosubstrate of drug metabolism. For example, the formation rate of sulfate conjugates of drugs is dependent on the concentration of the endogenous cosubstrated adenosine-3'-phosphate-5'-phosphosulfate. Project V will study the role of this cosubstrate in the interaction between acetaminophen and salicylamide. Project VI is concerned with a distinct class of drug interactions, i.e. those resulting from alterations in the intestinal microflora. The consequences of antibiotic treatment on the disposition of digoxin, warfarin and lorazepam will be elucidated. The interactions chosen for this program share the common characteristic that their mechanisms must be approached from a fundamental point of view. Such an approach can unravel the complexity of drug interactions and potentially lead to the development of general predictive principles.